Nitroxyl (HNO) has been shown to have positive cardiovascular effects in in vitro and in vivo models of failing hearts. However, at physiological pH, nitroxyl dimerizes to hyponitrous acid, which subsequently dehydrates to nitrous oxide. Owing to this metastability, nitroxyl for therapeutic use is typically generated in situ from donor compounds. A variety of compounds capable of donating nitroxyl have been described and proposed for use in treating disorders known or suspected to be responsive to nitroxyl. See, e.g., U.S. Pat. Nos. 6,936,639, 7,696,373, 8,030,356, 8,268,890, 8,227,639, and 8,318,705, U.S. pre-grant publication nos. 2009/0281067, 2009/0298795, 2011/0136827, and 2011/0144067, PCT international publication no. WO 2013/059194, and Paolocci et al., Pharmacol. Therapeutics 113:442-458 (2007). Although compounds in these references are disclosed to be capable of donating nitroxyl, they differ in various physicochemical properties and there remains a need to identify nitroxyl donors that have physicochemical properties best suited for treating specific clinical conditions via specific routes of administration.
Additionally, while nitroxyl donors for parenteral (e.g., intravenous) administration are currently being developed for clinical use, non-ideal solid state stability of the nitroxyl donors has impeded the development of oral dosage forms.
Accordingly, there is a need to provide nitroxyl donating compounds and compositions that are useful for the treatment of heart failure and that have a suitable safety profile. Moreover, there exists a need to provide nitroxyl donors that have increased solid state stability and, thus, are more amenable for oral administration.
Citation of any reference in Section 1 of this application is not to be construed as an admission that such reference is prior art to the present application.